5, 10-methylene-19-nor-androstanes



United States Patent 3,254,101 5,10-METHYLENE-19-NOR-ANDROSTANESLawrence H. Knox, Mexico City, Mexico, assignor to Syntex Corporation,Panama, Panama, a corporation of Panama N0 Drawing. Filed Feb. 20, 1964,Ser. No. 346,096 18 (Ilaims. (til. 260397.5)

The present invention relates to certain novel cyclopenotanophenanthrenederivatives and to the method for the production thereof.

More particularly, it relates to certain novel 5,10-methylene-l9-nor-androstan derivatives, substituted at C-3 or at C-1 and03 by lower alkyl, alkenyl or alkinyl radicals, and to the method forthe preparation of these compounds.

The novel compounds of the present invention are represented by thefollowing formulas:

OR3 OR3 z 1? 611 a 6G OR OR w M M08 In the above formulas R and Rrepresent a lower alkyl, alkenyl or alkinyl group such as methyl, ethyl,propyl, vinyl, propenyl, ethinyl, propinyl, etc.; R represents hydrogenor a lower alkyl, alkenyl or alkinyl group, R represent hydrogen or anacyl group of less than 12 carbon atoms and R and R represent a loweralkyl radical.

The acyl groups above referred to are derived from hydrocarboncarboxylic acids containing less than 12 carbon atoms which may besaturated or unsaturated, of straight, branched, cyclic orcyclicalip-hatic chain, or aromatic, and may be substitued by functionalgroups such as hydroxy,

v alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12carbon atoms, nitro, amino or halogen. Typical ester groups are theacetate, propionate, enant-hate, benzoate,trimethylacetate,t-butylacetate, phenoxyacetate,

cyclopentylpropionate, aminoacetate and fl-chloropropio- Patented May31, 1966 t ii .i

Ilka w J mi m a a. I

In the above formulas, R, R R R and R have the same meaning asheretofore set forth and R represents a lower alkyl, alkenyl or alkinylgroup.

In the practicing the process illustrated above, a laalkyl, alkenyl oralkinyl-S,lO-methylene-l9-norandrostan- 17B-ol-3-0ne compound (I)(obtained by reaction of 19- hydroxy-A -androstenc-la,17-dione withZ-chloro 1,1,2- trifluorotriethylamine, reduction of the 5,-10-methylene- 19-nor-A -androstene-3,l7-dione thus obtained with lithiumaluminum hydride, to produce 5,10- methylene-19- nor-A-androstene-3fl,17,8-diol, reoxidation of the hydroxyl group at G3 withmanganese dioxide to produce 5,10-methylene-l9-nor A -androsten17,8-ol-3-one and final treatment of the latter compound with an alkyl,alkenyl or alkinyl magnesium halide as described in our copending patentapplications Serial No. 286,931 filed June 11, 1963 now U. S. Pat. No.3,184,484 and Serial No. 346,074 filed of even date herewith) is reactedwith an aliphatic hydrocarbon magnesium halide such as VII methylmagnesium bromide, ethyl magnesium bromide, vinyl magnesium bromide,ethinyl magnesium bromide, propargyl magnesium bromide, etc. in an inertorganic solvent such as ether, benzene, tetrahydrofuran and the like, ata temperature comprised between room temperature and reflux, for aperiod of time between 1 to 6 hours to produce the corresponding3-alkyl, alkenyl, or alkinyl- 3-l1ydroxy-l-substituted-S,IO-methylene 19nor-androstan-17/3-ol-compounds (II), which are then dehydrated toproduce a mixture of 1,3-disubstituted-5,lO-methylene- 19-nor-A-andrsten-175-01 and 1,3 -disubst-ituted-5,l0- methylene l9 nor Aandrosten-l7p-ol (III and 1V, R =H), which are separated bychromatography on Florisil or neutral alumina.

These compounds can be conventionally esterified by treatment with acidanhydrides or chlorides of less than 12. carbon atoms in pyridinesolution, thus affording the corresponding esters (III and IV, R =acyl).

Catalytic hydrogenation of III and IV in the presence ofa heavy metalcatalyst, preferably in the presence of a palladium catalyst and in analcoholic solvent, produce the saturated compounds (V), by absorption of1 molar equivalent of hydrogen when R and R are lower alkyl groups, orfrom 2 to molar equivalents when R and/ or R are alkenyl or alkinylradicals. There are thus obtained mixtures ofla,3a-dialkyl-5,l0-methylene-l9-norandrostan-17fl-ols and1a,3fl-dialkyl-5,10-methylene-l9- nor-androstan-l7B-ols, the latterpredominating, which can be purified by fractional crystallization orchromatography. This hydrogenation is preferably conducted at roomtemperature and atmospheric pressure, however, these conditions are notcritical.

In order to obtain the 17-alkyl, alkenyl and alkinyl substitutedderivatives of the abovementioned compounds III, IV and V (R =H) areconverted into the respective -17-keto derivatives, by oxidation withchromic acid, and

these compounds are treated again with a Grignard reagent of the typehereinbefore indicated, or with an alkyl lithium or the sodium orpotassium salt of an alkine, to produce the respective1,3,17-trihydrocarbon substituted compounds (VI, VII and VIII; R =H),which can be converted into the corresponding esters by conventionaltreatment with acid anhydrides of less than 12 carbon atoms in benzenesolution and in the presence of p-toluenesulfonic acid.

The 3-alkyl, alkenyl or alkinyl substituted-5,10-seco- 5 ,19-cyclo-A-androstatrien-175 01 compounds or the corresponding 17a-alkyl, alkenylor alkinyl substituted derivatives thereof, described below (IX) andobtained as described in the aforementioned patent applications arehydrogenated in the presence of a heavy metal catalyst, using preferablya palladium-charcoal catalyst, in alcohol solution, and there areobtained, by absorption of from 2-to 6 molar equivalents of hydrogen,depending on the substituents at C-3 and/or C-l7a, the 3/3-alkyland 3B,17a-dialkyl-5,lO-methylene-19-nor-androstan-175-01 compounds in mixturewith the Bot-isomers (X):

OR OR li? I give rise to the corresponding Not-alkenyl or alkinyl-17,8-hydroxy derivatives, which can be converted into the correspondingesters by the above described method.

The Not-alkenyl compounds may also be obtained by partial hydrogenationof the Not-alkinyl derivatives.

The following examples serve to illustrate but are not intended to limitthe scope of the present invention:

Example I A solution of 2.5 g. of lot-methyl 5,1'0-methylene-19-nor-androstan-l7fl-ol-3-one in 95 cc. of ether was added- Example II Asolution of 1 g. of the foregoing compound in 7 cc. of dry pyridine wascooled to -10 0., treated with 0.4 cc. of thionyl chloride and themixture allowed to stand for 4 minutes at this temperature. Ice-waterwas added and the product extracted with methylene chloride. The organicextract was washed with water, hydrochloric acid solution, sodiumbicarbonate solution and water to neutral, dried over anhydrous sodiumsulfate and evaporated to dryness under reduced pressure. The residue 7was chromatographed on 50 g. on neutral alumina, thus producing1m,3-dimethyl-5,lO-methylene-l9-nor-A -androsten-17/3-ol, and1u,3-dimethyl-5,lO-methylene-19-nor-A androsten-lfiS-ol in pure form.

Example 111 By following the method of Example I, 1a-ethyl-5,10-methylene- 1 9-nor-androstanl 7B-o1-3-one, lopropyl-5 l 0-rnethylene-19-nor-androstan-l7/3-ol-3-one, 1a-vinyl-5,l0-methylene-l9-nor-androstan-17fi-ol-3-one and lot-ethinyl-5,10-methylene-l9-nor-androstan-17fl-o1-3-one were convertedrespectively into Ia-ethyl-B-methyl-S,10-methylene-19-nor-androstan-3,17;8-diol, lot-propyl 3 methyl-5,10-methylene-l9-nor-androstan-3,17,8-d-i0l, 1a-vinyl-3-methyl-5,1O-methylene-19-nor-androstan-3,l718-diol andlot-ethinyl-3-methyl-5,10-methylene-l9-nor-androstan-3,l7 8-diol.

These compounds were dehydrated in accordance with the method describedin Example II, to produce respectively:1a-ethyl-3-methyl-5,10-methylene-l9-nor-A androsten-l7fi-ol and:1a-ethyl-B-methyl-S,lO-methylene- 19 nor A androsten-17B-ol;1ot-propyl-3-methyl-5,10- methylene-l9-nor-A -androsten-173-01 and1a-propyl-3- methyl 5,10 methylene-l9-nor-A -androsten-l7fl-ol;10tvinyl-3 -methyl-5,IO-methylene-1'9-nor-A -androsteu-17,8-01 and1a-vinyl-3-methyl-5,l0-methylene-19-nor A androsten-17fi-ol;lwethinyl-B-methyl-S,l0-methylene-l9-nor- A -androsten-l7 3-ol and1a-ethinyl-3-methyl-5,10-methylene-l9-nor-A -androsten-1713-01.

Example IV A solution of 5 g. ofIa-methyl-S,l0-methylene-l9-norandrostan-l7fi-ol-3-one in 250 cc. ofthiophene-free benzene was treated with 27.5 cc. of 4 N methylmagnesiumbromide in ether and the mixture refluxed with the exclusion of moisturefor 3 hours. The cooled mixture was cautiously treated with excessaqueous ammonium chloride solution and the product isolated by ethylacetate extraction. The extract was washed with water, dried overanhydrous sodium sulfate and evaporated to dryness.

Recrystallization from methylene chloride-hexane afforded 1a,3-dimethyl-5 1 O-methylenel 9-nor-androstane- 3,17/3-diol, identicalto that'obtained in Example I.

' 6 1a-ethyl-3B-methyl-5,10-methy1ene-19-norandrostan- 1713-01,

I Reagent 1a-ethy1-5, -methylene-l9-nor-androstan-17 S-ol-3-onela-propyl-5,10-methylene-19-n0r-androstan-17fl-ol-3-one.

1a-vinyl-s,lo-methylene-19-nor-androstan-17/3-ol-3-onela-ethinyl-5,lO-methylene-lQ-nor-an drostan-17B-ol3-one Vinylmagnesiumbromide Ethylmagnesium bromide.

Propylmagnesium bromide Ethinylmagnesium bromide 1aeigl11yl-3-vinyl-5,10methylene-lQ-nor-androstane-S,17B-lapglepyl-li-ethyl-a10-methylene-19-nor-androstane-3,17 8-laiilp'yl-3-propyl-5,IO-methylene-19-nor-androstane-3,175-1a,3'diethiny1-5,10-methylene-19-nor-androstane-3,llfi-diol.

la-propenyl-fi,ID-methylene-l9-nor-androstan-17fi-ol-3-oneMethylmagnesium bromide. laplrppgnyil-amethyl-s,IO-methylene-19-nor-androstane- ,6- i0.1a-propinyl-5,lO-methylene-lQ-nor-androstan-17fi-ol-3-oneEthylmag11es1umbrom1de lairopiinyl-3-ethyl-5,lfl-methylene-lQ-nor-androstane- 7 i1a-metliyl-fi,IO-methylene-l9-nor-androstan-l7fl-ol-3-oneEthinylmagnesium bromide.la-inethyl-ii-ethinyl-s,10-methylene-19-nor-androstane 3,176 diolExample V Into a suspension of 1 g. of1ot-3-dimethyl-5,IO-methylene-l9-nor-androstane-3/3,17,8-diol in 35 cc.of glacial acetic acid, was passed a slow stream of dry hydrochloricacid; after 10 minutes all the solid material was dissolved. The gas waspassed through the reaction mixture for a total of 5 hours. The solutionwas concentrated to about one third its initial volume by distillationunder reduced pressure at 35 C., then it was poured into ice-water. Theproduct was extracted with ether, washed to neutral, dried andevaporated to dryness. Chromatography of the residue on 50 g. offlorisil afiorded 1a,3-dimethyl-5, 1O-methylene-l9-nor-A-androsten-17,8-01 and 1a,3di methyl-5,1O-methylene-19-nor-A-androsten-17fl-ol in pure form, identical to the products obtained bythe method of Example II.

In the same manner, the rest of the products obtained in the precedingexample were converted respectively into: 10c ethyl 3vinyl-5,1O-rnethylene-19-nor-A -androsten- 175-01 and1a-ethyl-3-vinyl-5,l0-methylene-l9-nor-A androsten-17/3-ol;1ot-propyl-3-ethyl-5,10 methylene 19- nor-A -androsten-17fi-o1 and1a-propyl-3-ethyl-5,IO-methylene-l9-nor-A -androsten-175-01;1u-vinyl-3-propyl-5,10- methylene-l9-nor-A -andr0sten-175-01 andlot-vinyl-3-propyl-S,lO-methylene-19-nor-A -androsten-175-01; 1cc,3diethinyl 5,10 methylene-19-nor-A -andr0sten-175-01 andloc,3-diethinyl-5,1O-methylene-19-nor-A -androsten-1713-01; 1a propenyl3-methyl-5,1O-methylene-l9-nor-A -androsten-17B-ol and1a-propenyl-3-methyl-5,10-methylene-19- nor-A -androsten-17,8-01;1a-propinyl-3-ethyl-5,IO-methylene-l9-nor-A androsten-175-ol andlu-propinyl-3-ethyl-5, 1O methylene l9-nor-A -androsten-17,6-01;Ia-methyl-S- ethinyl 5,10 methylene-l9-nor-A -androsten-175-01 and1ot-methyl-3-ethinyl-5,IO-methylene 19 nor A androsten-17fl-ol.

Example VI In accordance with the hydrogenation method described in thepreceding example,

1ot-ethyl-3-methyl-5,10-methy1ene-l9-nor-A androsten-l7 8-ol,

1e-propyl-3-methyl-5,10-methylene-19-nor-A androsten-175-ol and1a-propyl-3 ethyl-5,10-methylene-19'-nor-A androsten- 17/3-01 wereconverted into the corresponding saturated derivatives, namely1a-propyl-3/3-methyl-5,10-methylene-l9-norandrostan-17B-ol and1a-propyl-3fl-ethyl-5,10-methylene-l9-nor-androstan- Example VIII Asolution of 2 g. of 1a-ethinyl-3-methy1-5,10-methylene-l9-n or-A aandroszten-17,8-01 in 250 cc. of ethanol was hydrogenated in the presence of200 mg. of 10% palladium charcoal catalyst, until the absorption ofhydrogen ceased (3 molar equivalents). The catalyst was removed byfiltration and the filtrate evaporated to dryness under reducedpressure. The residue was crystallized from acetone-ether, thusproducing 1u,3B-dimethyl- 5,10-methylene-l9-nor-androstan-17fl-olidentical to that obtained in Example VI.

In a similar manner, 1a-propinyl-3-ethyl-5,10-methy1- ene-19-nor-A-androsten-1713-01 was converted into 1apropyl-3p-ethyl-5,10-methylene-19-nor-androstan-17,6 01, identical to the product obtained in ExampleVII.

Example IX In the method of the preceding example there was used1ot-vinyl-3-methyl-5,1O'-methylene19-nor-A androsten-17fi-ol as startingmaterial, and the uptake of hydrogen was of 2 molar equivalents. Therewas thus obtained 1u-ethyl3,8-methy1-5,10-methy1ene-19 norandrostan-17/3-ol, identical to that obtained in Example VII.

Example X Example XI A solution of 1 g. of 1a,3-dimethy1-5,IO-methylene-19-n0r-A -androsten-176-01 in 10 cc. of acetone was cooled to 0 C. andtreated under an atmosphere of nitrogen and with stirring, with asolution of 8 N chromic acid (prepared by mixing 26 g. of chromiumtrioxide with 23 cc. of concentrated sulfuric acid and diluting withwater to cc.), until the color of the reagent persisted in the mixture.It was stirred for 5 minutes further at 0-5 C. and diluted with water.The precipitate was collected, washed with water and dried under vacuum,thus affordwere C011- ing a crude product which upon recrystalliaztionfrom acetone-hexane gave la,3-dimethy1-5,l0-methylene-19- nor-A-androsten-17-one.

The preceding compound was then treated with methyl magnesium bromide byfollowing the method of Example IV, thus producing1a,3,17a-trimethyl-5,lO-methylene-l9- nor-A -androsten-17fl-ol.

Example XII By following the oxidation method described in the precedingexample the compounds mentioned below under I were converted into thecorresponding 17 ketones (II):

1a-ethy1-3-vinyl-5,10methylene 19-nor-N-androsten-Ufi-ol.

1a-pr0penyl-3-methyl-5,IO-methyL ene-IQ-nor-N-androsten-17B-0l.

la-methyl-3-ethiuyl-5,10methylene-lQ-nOr-A -andrQSterA-l76-01.1a-propyl-3-ethyl-5,10-methylene l9-nor-A -andrsten-17B-0l.1a-vinyl-3-propyl-5,IO-methylene- 19-nor-A -a-ndrosten-175ml.1a-propinyl-3-ethyl-5,lo methylenc-lQ-nor-A -androsten-17B-ol.1a,3fl-dimethy1-5,lO-methylene-19- nor-audrostan-Ufl-ol.1a-propyl-3fl-metl1yl-5,IO-methylene-19-nor-andr0stan-l7B-ol.1a-ethyl-3fl-methyl-5,lO-methylene-19-nor'androstan-l7B-0l.1a-pr0py1-3B-ethyl-5,lO-methylene-19-n0r-androstan-175-ol.

I Reagent 8 Example XIV To a solution of 2 g. of1a,3-dimethyl-5,10-methylene- 19-nor-A -androsten-17-one in 250 cc. ofabsolute ether was added dropwise, a solution of 10 molar equivalents ofethyl lithium in cc. of ether with mechanical stirring and under anatmosphere of nitrogen. The mixture was further stirred for 48 hours atroom temperature. After pouring into water, the resulting mixture wasacidi fied with hydrochloric acid, stirring vigorously for 1 hour. Theether layer was separated, washed with water to neutral, dried overanhydrous sodium sulfate, filtered and the ether was evaporated todryness. Recrystallization of the residue from acetone-hexane yielded'1oc,3-dimethyl- 17ot-ethyl-5,1O-methylene-l9-nor-A -androsten-17fiol.

In a similar manner, 1a-propenyl-3-methyl-5,10-methylene-l9-nor-A-androsten-17-one, '1a-vinyl-3-propyl-5,l0 methylene-19-nor-A-androsten-l7-one andla-propyl-3flethyle5,lO-methylene-l9-nor-androstan-17-one, wereconverted respectively into 1a-propenyl-3-methyl-17nt-ethyl- 5,10methylene l9-nor-A -androsten-l7fi-ol, -1oc-vinyl-3-propyl-17ot-ethyl-5, 10-methylene-19-nor A androsten- 175-01 andI1a-propyl-3fl,l7a-diethyl-5,lO-methylene-19- nor-androstan-17fi-ol.

Example XV By following the method of Example IV, the compoundsmentioned below under I were treated with the indicated Grignardreagent, thus producing the compounds mentioned under II:

1a-methyl-3-ethinyl-5,10-methylene-lQ-nor-N-androsten- Methylmague siumbromide 1a-propinyl-3-ethyl-5,l0-methylene-19-nor-A -androsten-Propargylmagnesium 1a,l7a-dipropinyl-3-ethyl-5,l0-methylene-19-n0r-A17-0ne. bromide. androsten-Ufl-ol.1a-pr0pyl-3fi-methyl-5,10-methylene-lQ-nor-androstan- Vinylmagnesiumbromide... la-propyl-3B-rnethy1-17a-vinyl-5,lO-methylene-lQ-norl7-0ne.androstan-Ufl-ol. 1a-ethyl-3B-methyl-5,10-methylene-lQ-nor-androstan-l7-Propenylmagnesium1a-ethyl-3B-methyl-17a-pr0penyl-5,10-methylene-l9-n0rone. bromide.androstau-UB-ol. 1a,3 3-dimethyl-S,IO-methylene-lQ-nor-androstan-17-one.Vinylmagnesium bromide.-.la,3fl-dimethyl-17a-vinyl-5,l0-methylene-19-nor-andro- Stan-176ml.

Example XIII A solution of l g. of 1a,3-dimethyl-5,IO-methylene-19-nor-A -andr-osteml7-one in 30 ccjof anhydrous benzene was added,under nitrogen, to a solution prepared by dissolving =1:4 g. ofpotassium in 30 cc. of t-amyl alcohol. A slow current of purifiedacetylene was passed through the solution for 40 hours, whereupon thesolution was diluted with water and extracted with benzene. The organicextracts were then washed to neutral and dried over anhydrous sodiumsulfate. Evaporation of the solvent and chromatography of the residue on70 g. of alkaline alumina gave in the hexane-benzene (2:3) fractions aproduct, which upon recrystallization from ace- Example XVI Inaccordance with the method described in Example X, 104,3 dimethyl5,'l0-methylene-19-nor-A -androsten- 176-01,1a-ethinyl-B-methyl-ilO-rnethylene-l9-nor-A -androsten 17,8-ol and1u-ethyl-3fi-methyl-5,lO-methylene- -19-nor-androstan-l7B-ol weretreated with propionic,

caproic and cyclopentyl-propionic anhydrides to produce thecorresponding esters.

Example XVII To a solution of 500 mg. of l1m,3,17u-trimethyl-5,10-

methylene-19-nor-A -androsten-175-01, in 10 cc. of anhydrous benzenethere were added mg. of p-toluenesulfonic acid and 1.5 cc. of aceticanhydride and the mixture was allowed to stand for 24 hours at roomtemperature, poured into ice and water, and the resulting mixturestirred to effect hydrolysis of the excess anhydride. The benzene layerwas separated and washed with 10% sodium carbonate solution and water.Drying, evaporation and crystallization of the residue from ether-hexaneproduced the acetate of la,3,l7ot-trimethyl-5,lO-methylene-l9-nor-A-androsten-l75-01.

By the same method, la,l7a-dipropinyl 3-ethyl-5,10- methylene 19-nor-A-androstenl7/3-01, 1d,].76t-dlm6thy1- stan-17B-ol were converted intothe corresponding ace -5,10-methylene-l9-nor-androstan-176-01 and 3,B-propyl- 5,lO-methylene-19-nor-androstan--17,8-01 were oxidized with 8N chromic acid in acetone solution, to produce tates, respectively:3fi-methyl-5,10-methylene-19-nor-androstan- E l XVIII 17-one,3B-ethyl-5,l0-methylene-l9-nor-androstan-17-one and3fi-propyl-5,10-methylene-19-nor-androstan-l7-one. A solution of 1 g. of3-methyl-5,10-seco-5, l9-cyclo- A -androstatrien-17,8-01 in 50 cc. ofethanol was Example XXI mixed with 250 mg. of a 10% palladium oncharcoal The compounds obtained in the preceding example were catalyst.The mixture was hydrogenated at room tem- 10 treated with potassiumacetylide, in accordance with the perature, at atmospheric pressure,until the absorption of method of Example XIII, to produce respectively:3/3- hydrogen ceased (approximately 2 molar equivalents ofmethyl-l7u-ethinyl-5,lO-methylene 19 nor androstanhydrogen wereabsorbed). The catalyst was removed by 175-01,3fi-ethyl-l7a-ethinyl-5,lO-methylfine-19nor-androfiltration, and thesolvent evaporated under reduced presstan-17fl-ol and3fi-propyl-l7a-ethinyl-5,10-methylene-19- sure, water was added to theresidue and the product was nor-androstan-17fl-ol. extracted withmethylene clfloride. The extract was washed with water, dried overanhydrous sodium sulfate Example XXII and evaporated to dryness undervacuum. Crystalliza- A solution of 1 g. of3/3-methyl-17a-ethinyl-5,IO-methyltion from acetone-hexane afforded3,B-methyl-5,l0-methylene-19-nor-androstan-175-01, in 40 cc. of pyridinewas ene-l9-nor-androstan-l7,8-01. 20 hydrogenated at C. and 570 mm. inthe presence of By the same method, the compounds mentioned below 400mg. of pre-hydrogenated 2% palladium calcium carunder I were convertedinto the saturated compounds bonate catalyst. listed under II: When 1.1molar equivalents of hydrogen had been absorbed, the reaction wasstopped, the catalyst separated I H 25 by filtration through celite,washed with ethyl acetate and the combined solutions evaporated todryness in vacuo, 3 ethyl s,w seco 5y1943mm methymy10 methy1ene 19yielding the crude vinyl derivative. This crude product A-androstatriendm-ol. nor-androstan-Hfl-ol. was dissolved 1n ethylacetate, the organic solution washed 'afiigggfgggfggg 3:223: tg ggggijggg With dilute hydrochloric acid and water to neutral, dried3,gcggifigilgllggkfigig??}?6i5y01O- Bflggggigegggffirgfihyleneandevaporated to dryness. Recrystalllzation from ace-3,17a-diethyl-5,10-seco-5:19-cyclo-- 3B,17u-diethyl-5,10-methy1ene-19-tone gave 3/3'methy1'17"Vmy15lo'methylenel9'nor'an A-androstatricu-l73-01. nor-androstan-Nfl-ol. drostan-17f3-ol.

In a similar manner,3p-ethyl-l7a-ethinyl-5,lO-methylene-l9-nor-androstan-l7 8-ol and3fi-propyl-l7a-ethinyl- Example XIX5,lO-methylene-l9-nor-androstan-l713-01 were converted A solution of 1g. of 3-ethinyl-5,10-seco-5,19-cycloi fiy y A -androstatrien-175-01 in70 cc. of methanol was 17/3-01and fi-P PY Y y hydrogenated in thepresence of 500 mg. of 10% palladium drostan-17/3-ol respectively.charcoal catalyst until the uptake of hydrogen ceased. The catalyst wasfiltered oil and the filtrate evaporated 40 Example XXIII to dryness.The residue was crystallized from acetone- By following the method ofExample X, 3B-methy1-5,10- ether, to produce3-ethyl-5,lO-methylene-l9-nor-andromethylene-l9 nor-androstan-l7fl-ol,3/3-ethy1-5,10amethylstan-l7/3-ol, identical to the product obtainedfrom 3- ene-19-nor-androstan-17/3-ol and 3fl-propyl-5,l0-methylethyl-5,1O-seco-5,l9-cyclo-A -androStatrien- 17/8- 01,ene-l9-nor-androstan-17fl-ol, were treated with acetic, in the previousexample. propionic and undecenoic anhydride in pyridine solution, In asimilar manner, starting from 3,l7a-divinyl-5,10- to produce thecorresponding acetates, propionates and seco-S,19-cyclo-A-androstatrien-1718-01 there was undecenoates. produced35,17a-diethyl-5,10-methylene l9 nor-andro- Example XXIV stan-l7fl-ol,identical to that obtained in Example XIV.

By following the method of Example XVII, the com- Emmple XX poundsmentioned below under I were treated with the In accordance with themethod of Example XI, 35- indicated acid anhydride, to produce thecorresponding methyl-5,lO-methylene-19-nor-androstan-17,8-01,3,3-ethylesters (II):

I Anhydride II 3,6,17a-dimethyl-5,IO-methylene-l9-nor-androstan-17B-ol.Propionie Proponatt 01173flil7a-dimethyl-5,10-methylene-19-nor-36,17a-diethyl-5,10-methylene-19-n0r-androstan-17fl-o1 Acetic. Aggraizeioi gfl,I zZdiethyl-S,10-methylene-19-n0r-androstan-35ig1ethyl-17a-ethinyl-5,1O-methylene-lQ-nor-androstan- Caproic Cap ioate of 3/3-methyl-17u-ethinyl-5,10-methylene49-nor-3,3-cthyl-17a-vinyl-5,10-methylene-l9-nor-androstan-17fl-olCyclopentylpropionic cgz ge ri y lpz p i onate of 3fiethy1-17a-viny1-5,10-methy1- ene-19-nor-androstan-17 5-ol.36-pr0pyl-17a-ethinyl-5,10-methylene-lQ-nor-androstan- Acetic. AcetateofB S-propyl-17a-ethinyl-5,IO-methylene-lQ-nor- 173-01.androstan-lWS-clv 101-17wdimethyl-3-cthinyl-5,IO-methylene 19-n0r-APropicnic Propionate of1a,17a-dimethyl-3-ethinyl-5,ld-methyleneandrosten-HB-ol. 19-nor-A-androsten-17fl-ol. 1a,17t-di ro inyl-3-ethy1-5,10-methy1ene-19-nor-ACaproic Caproate of 1a,17a-di-propinyl-3-ethyl-5,10-methy1ene-19-androsten-17fl-ol. nor-A -androsten-17B-ol.1a-propyl-3fl-methyl-l7a-vinyl-5,10-methylene-19-nor- EnanthicEnanthateof1a-propy1-3B-methy1-17a-vinyl-5,IO-methylandrostan-Hdol.ene-l9-nor-androstan-17fl-ol.1a-ethyl-3fi-methyl-17a-propenyl-5,10-methylene-19-n0r-Cyclopentylpropionic Cyclopentylpropionatcof1a-ethyl-3fi-methyl-17aandr0stan-l7B-ol.propenyl-5,10-methylene-lQ-nor-androstan-l7fl-ol.1a,3fl-dimethyl-17a-vinyl-5,10-methylene-19-nor- Propionic Propionate of1o ,3fl-dimethyl-17a-viny1-5,IO-methyleneandrostan-l'Yfl-ol. l-nor-androstamflfl-ol.

I claim: 1. A compound of the following formula:

wherein R and R are selected from the group consisting of lower alkyl,lower alkenyl and lower alkinyl; R is selected from the group consistingof hydrogen, lower alkyl, lower alkenyl and lower alkinyl and R isselected from a group consisting of hydrogen and a hydrocarboncarboxylic acyl group of less than 12 carbon atoms.

2. 1u,3 dimethyl 5,10 methylene 19 nor A androsten-17/3-ol.

3. 1a,3,17oc trimethyl 5,10 methylene 19 nor- A -androsten-17fl-ol.

4. 1m methyl 3 ethinyl 5,10 methylene 19 nor- A -androsten-l'l'fi-ol.

5. 1a,17a dimethyl 3 ethynyl 5,10 methylene- 19-nor-A androsten-175-01.

6. A compound of the following formula:

wherein R'and R are selected from the group consisting of lower alkyl,lower alkenyl and lower alkinyl; R is selected from the group consistingof hydrogen, lower alkyl, lower alkenyl and lower alkinyl and R isselected from the group consisting of hydrogen and a hydrocarboncarboxylic acyl group of less than 12 carbon atoms.

7. c,3 dimethyl 5,10 methylene 19 nor A androsten-17B-ol.

8. 1o: ethyl 3 methyl 5,10 methylene 19 nor- A -androsten-17B-ol.

9. 1oc,17oc dipropinyl 3 ethyl 5,10 methylene 19- nor-A-androsten-17fl-ol.

10. 10c propyl 3 ethyl 17a ethinyl 5,10 methylene-19-nor-A-androsten-175-01.

11. A compound of the following formula:

wherein R -is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl and lower alkinyl and R is selected from the groupconsisting of hydrogen and a hydrocarbon carboxylic acyl group of lessthan 12 carbon atoms; and R represents a lower alkyl radical.

12. 3,8 methyl 5,10 methylene 19 norandrostan-17/3-ol.

13. 3/3 propyl 5,10 methylene 19 nor androstan-17 8-ol.

14. 35,170; dimethyl 5,10 methylene 19 nor androstan-17/3-ol.

15. 3B methyl 17a ethinyl 5,10 methylene l9- nor-androstan-17fi-ol.

16. A compound of the following formula:

No references cited.

LEWIS GOTTS, Primary Examiner. HENRY A. FRENCH, Assistant Examiner.

1. A COMPOUND OF THE FOLLOWING FORMULA: